Innate Immune Mechanisms at the Maternal-Fetal Interface in Normal and Superovulatory Pregnancy

正常和超排卵妊娠母胎界面的先天免疫机制

• 批准号: 10222493
• 负责人: Aimee Melissa Beaulieu
• 金额: $ 77.06万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-21 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10222493
• 关键词: Area; Birth; Blood Vessels; Cell physiology; Cells; Child; Data; Decidual Cell Reactions; Development; Diagnostic; Disease; Early Diagnosis; Emotional; Endometrial; Epithelial; Epithelial Cells; Event; Family; Fertilization in Vitro; Fetal Growth; Fetal Growth Retardation; Financial cost; Foundations; Functional disorder; Habitual Abortion; Health; Heterogeneity; Human; Immune; Immune System Diseases; Immune response; Impairment; In Vitro; Inflammatory Response; Interferon Type II; Interleukin-1; Knockout Mice; Lead; Link; Low Birth Weight Infant; Macrophage Activation; Maternal-Fetal Exchange; Mediating; Molecular; Mothers; Mus; Natural Killer Cells; Neonatal; Outcome; Ovarian; Ovarian Stimulations; Placenta; Placental Insufficiency; Placentation; Play; Population; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnancy loss; Prevention; Process; Production; Protocols documentation; Public Health; Recurrence; Risk; Role; Sampling; Signal Transduction; Superovulation; Testing; Therapeutic; Tissues; Uterus; Vascular Endothelial Growth Factors; Vascularization; Woman; angiogenesis; cost; cytokine; early pregnancy; fetal; fetal loss; healthy pregnancy; immune function; implantation; improved; in vivo; innate immune mechanisms; macrophage; mouse model; natural Blastocyst Implantation; placental morphology; pleiotropism; pregnancy disorder; pregnant; receptor; tool development

Project Summary/Abstract Placental insufficiency underlies many pregnancy disorders, including preeclampsia (PE), intrauterine growth restriction (IUGR) and recurrent pregnancy loss (RPL). Collectively, these disorders have costly, widespread, and sometimes long term, health consequences for the mother and/or child. Immune cell populations at the maternal-fetal interface, including uterine natural killer cells (uNKs) and uterine macrophages (uMacs), mediate angiogenesis and other key events in decidualization, placentation, and progression of pregnancy. Dysregulated inflammatory responses during decidualization or placentation have been linked to PE, IUGR, and RPL. Moreover, a growing number of births in the US are achieved using controlled ovarian stimulation (“superovulation”) protocols for in vitro fertilization (IVF), which is associated with dysregulated uterine immune cell function and increased risk of pregnancy complications due to placental dysfunction. The molecular mechanisms that regulate immune cell function at the maternal-fetal interface are poorly understood. Recent studies have highlighted critical roles for the IL-1 family cytokine, IL-33, in pregnancy, and aberrant maternal IL-33 signaling has been linked to RPL and PE in humans. Our preliminary data reveal numerous IL-33-expressing cells, including many IL-33+ uterine epithlelial cells, in the murine uterus at key stages of pregnancy. These IL-33+ cells are located in immune cell-rich regions heavily populated by uNKs and uMacs. Although IL-33 regulates key aspects of NK and Mac function in other tissues, its specific effects on uNKs and uMacs remains poorly understood. We hypothesize that IL-33 signaling supports decidualization and placentation by promoting uNK and uMac-mediated angiogenesis and tissue remodeling during pregnancy. Guided by this hypothesis, our proposed studies aim to: (1) Define the role of IL-33 signaling in pregnancy progression. We will utilize mice that lack IL-33 globally or in uterine epithelial cells, or mice in which IL-33 is neutralized at key stages of gestation, to define the role of IL-33 in decidualization, placental formation and placental function during pregnancy. (2) Determine the effects of IL-33 signaling on NK and Mac function at the maternal-fetal interface. We will use complementary in vitro approaches and in vivo studies in IL-33-deficient mice to determine how IL-33 signaling regulates the angiogenic and tissue remodeling activities of uNKs and uMacs during pregnancy. (3) Determine the impact of superovulation (SO) on uNK and uMac function. We will use mouse models of SO, in combination with studies on primary human endometrial samples from women undergoing SO for IVF, to investigate the impact of SO on IL-33-dependent and –independent uNK and uMac effector functions.

项目摘要/摘要 胎盘不足是许多妊娠疾病的基础，包括先兆子痫（PE），内部生长 限制（IUGR）和复发性怀孕丧失（RPL）。总的来说，这些疾病具有昂贵的，宽度的范围， 有时长期，母亲和/或孩子的健康后果。免疫细胞种群 母亲界界面，包括子宫天然杀手细胞（UNK）和子宫巨噬细胞（UMAC），培养基 妊娠决策，安置和进展中的血管生成和其他关键事件。 决定性化或放置期间的炎症反应失调与PE，IUGR有关 和Rpl。此外，使用受控的卵巢刺激，在美国越来越多的出生 （“超排除”）体外受精（IVF）方案，该方案与子宫免疫失调有关 细胞功能和由于胎盘功能障碍引起的妊娠并发症的风险增加。 调节在母乳界面上免疫功能功能的分子机制较差 理解。最近的研究强调了IL-1家族细胞因子，IL-33在怀孕中的关键作用，以及 异常的母校IL-33信号传导与人类的RPL和PE有关。我们的初步数据显示 在钥匙处的鼠子宫中，许多表达IL-33的细胞，包括许多IL-33+子宫上皮细胞 怀孕阶段。这些IL-33+细胞位于UNK大量人群的富含免疫细胞的区域 尽管IL-33调节了其他组织中NK和MAC功能的关键方面，但其特定效果 在UNK和UMAC上，人们的理解仍然很差。我们假设IL-33信号支持决策 通过促进UNK和UMAC介导的血管生成和组织重塑来放置 怀孕。在这一假设的指导下，我们提出的研究旨在： （1）定义IL-33信号传导在妊娠进展中的作用。我们将利用全球缺乏IL-33的小鼠 或在子宫上皮细胞中，或在妊娠关键阶段中和的小鼠，以定义 IL-33在怀孕期间的决策，占地形成和占位术功能。 （2）确定IL-33信号传导对母亲界界面上NK和MAC功能的影响。我们 将使用IL-33缺陷小鼠的体外方法和体内研究来确定IL-33如何 信号传导调节怀孕期间UNK和UMAC的血管生成和组织重塑活性。 （3）确定超排除（SO）对UNK和UMAC功能的影响。我们将使用鼠标模型 因此，结合对经历的妇女原发性人子宫内膜样本的研究， IVF，研究SO对IL-33依赖性和非依赖性UNK和UMAC效应子功能的影响。